NM_153046.3:c.43A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153046.3(TDRD9):​c.43A>G​(p.Thr15Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000288 in 1,389,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Publications

0 publications found
Variant links:
Genes affected
TDRD9 (HGNC:20122): (tudor domain containing 9) Predicted to enable RNA binding activity. Involved in spermatogenesis. Located in cytoplasm and nucleus. Implicated in spermatogenic failure 30. [provided by Alliance of Genome Resources, Apr 2022]
TDRD9 Gene-Disease associations (from GenCC):
  • spermatogenic failure 30
    Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • male infertility with azoospermia or oligozoospermia due to single gene mutation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20539925).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TDRD9NM_153046.3 linkc.43A>G p.Thr15Ala missense_variant Exon 1 of 36 ENST00000409874.9 NP_694591.2 Q8NDG6-1Q86WA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TDRD9ENST00000409874.9 linkc.43A>G p.Thr15Ala missense_variant Exon 1 of 36 5 NM_153046.3 ENSP00000387303.4 Q8NDG6-1

Frequencies

GnomAD3 genomes
AF:
0.0000199
AC:
3
AN:
150442
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000727
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
66808
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
8.07e-7
AC:
1
AN:
1238638
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
608208
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
24140
American (AMR)
AF:
0.00
AC:
0
AN:
16916
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19188
East Asian (EAS)
AF:
0.0000389
AC:
1
AN:
25714
South Asian (SAS)
AF:
0.00
AC:
0
AN:
63448
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
44516
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4924
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
991180
Other (OTH)
AF:
0.00
AC:
0
AN:
48612
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.0000199
AC:
3
AN:
150442
Hom.:
0
Cov.:
31
AF XY:
0.0000136
AC XY:
1
AN XY:
73386
show subpopulations
African (AFR)
AF:
0.0000727
AC:
3
AN:
41262
American (AMR)
AF:
0.00
AC:
0
AN:
15128
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3442
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9912
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67408
Other (OTH)
AF:
0.00
AC:
0
AN:
2070
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.558
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000334
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 04, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.43A>G (p.T15A) alteration is located in exon 1 (coding exon 1) of the TDRD9 gene. This alteration results from a A to G substitution at nucleotide position 43, causing the threonine (T) at amino acid position 15 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.031
T
Eigen
Benign
0.00068
Eigen_PC
Benign
0.097
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.45
T
M_CAP
Uncertain
0.096
D
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
L
PhyloP100
4.5
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.99
N
REVEL
Benign
0.11
Sift
Uncertain
0.012
D
Sift4G
Benign
0.32
T
Polyphen
0.77
P
Vest4
0.33
MVP
0.15
MPC
0.79
ClinPred
0.56
D
GERP RS
3.6
PromoterAI
0.14
Neutral
Varity_R
0.13
gMVP
0.61
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1036038741; hg19: chr14-104394889; API